Ligand binding promotes prion protein aggregation - role of the octapeptide repeats

Department of Pathology, Case Western Reserve University, Cleveland, OH 44106-7288, USA.
FEBS Journal (Impact Factor: 3.99). 12/2008; 275(22):5564-75. DOI: 10.1111/j.1742-4658.2008.06680.x
Source: PubMed

ABSTRACT Aggregation of the normal cellular prion protein, PrP, is important in the pathogenesis of prion disease. PrP binds glycosaminoglycan (GAG) and divalent cations, such as Cu(2+) and Zn(2+). Here, we report our findings that GAG and Cu(2+) promote the aggregation of recombinant human PrP (rPrP). The normal cellular prion protein has five octapeptide repeats. In the presence of either GAG or Cu(2+), mutant rPrPs with eight or ten octapeptide repeats are more aggregation prone, exhibit faster kinetics and form larger aggregates than wild-type PrP. When the GAG-binding motif, KKRPK, is deleted the effect of GAG but not that of Cu(2+) is abolished. By contrast, when the Cu(2+)-binding motif, the octapeptide-repeat region, is deleted, neither GAG nor Cu(2+) is able to promote aggregation. Therefore, the octapeptide-repeat region is critical in the aggregation of rPrP, irrespective of the promoting ligand. Furthermore, aggregation of rPrP in the presence of GAG is blocked with anti-PrP mAbs, whereas none of the tested anti-PrP mAbs block Cu(2+)-promoted aggregation. However, a mAb that is specific for an epitope at the N-terminus enhances aggregation in the presence of either GAG or Cu(2+). Therefore, although binding of either GAG or Cu(2+) promotes the aggregation of rPrP, their aggregation processes are different, suggesting multiple pathways of rPrP aggregation.

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Available from: Robert B Petersen, Jul 22, 2015
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    • "Indeed, Cu was found to induce expression of cellular PrP in primary cell cultures, upregulating the expression of this protein both at the cell surface as well as within intracellular compartments [116]. Cu promotes the aggregation of human PrP [117]. These findings stimulated the investigations on metal ion alteration in PrD human brains. "
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    • "ion per repeat (Viles et al. 2008; Guerrieri et al. 2009), but there is still no generally accepted role for the binding of copper to PrP (Davies and Brown 2008). The repeat region modulates prion replication and pathogenicity (Flechsig et al. 2000), is involved in the protective effect against oxidative stress (Mitteregger et al. 2007; Malaise et al. 2008), and in PrP aggregation upon copper binding (Yu et al. 2008). Mammals homozygous for four or seven repeats also occur (van Rheede et al. 2003; Kim et al. 2008; Rongyan et al. 2008; Martin et al. 2009). "
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